CN101180128B - Optical assay system - Google Patents
Optical assay system Download PDFInfo
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- CN101180128B CN101180128B CN200680017677XA CN200680017677A CN101180128B CN 101180128 B CN101180128 B CN 101180128B CN 200680017677X A CN200680017677X A CN 200680017677XA CN 200680017677 A CN200680017677 A CN 200680017677A CN 101180128 B CN101180128 B CN 101180128B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
- G02B6/24—Coupling light guides
- G02B6/26—Optical coupling means
- G02B6/28—Optical coupling means having data bus means, i.e. plural waveguides interconnected and providing an inherently bidirectional system by mixing and splitting signals
- G02B6/2804—Optical coupling means having data bus means, i.e. plural waveguides interconnected and providing an inherently bidirectional system by mixing and splitting signals forming multipart couplers without wavelength selective elements, e.g. "T" couplers, star couplers
- G02B6/2852—Optical coupling means having data bus means, i.e. plural waveguides interconnected and providing an inherently bidirectional system by mixing and splitting signals forming multipart couplers without wavelength selective elements, e.g. "T" couplers, star couplers using tapping light guides arranged sidewardly, e.g. in a non-parallel relationship with respect to the bus light guides (light extraction or launching through cladding, with or without surface discontinuities, bent structures)
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0654—Lenses; Optical fibres
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0822—Slides
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/08—Regulating or influencing the flow resistance
- B01L2400/084—Passive control of flow resistance
- B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
Abstract
Optical reader (33, 43, 53, 63, 73, 83) for an optical assay arrangement comprises a polymeric sample substrate (1) having a reaction site-area (5) provided with protruding microstructures (2), the optical reader comprising a light source (6, 11) for illuminating the reaction site-area (5), and a detector device (7, 12) for detecting light emitted from said reaction site-area.
Description
Technical field
The present invention relates to comprise and be provided with for example improvement optical pickup (optical reader) used of the device for the optical evaluation of the polymeric sample substrate of microtrabeculae (micropillar) of outstanding micro-structural.The invention still further relates to the polymeric sample substrate that is provided with outstanding micro-structural, and comprise device for the optical evaluation according to optical pickup of the present invention and polymeric sample substrate.
Background technology
By based on optical assay, can analyze and diagnostic assay fluid sample to the detection of analyte in the sample of for example polynucleotides analyte, receptor protein or counter ligand (antiligand) molecule.An important application of optical assay is immune field, wherein detect this analyte by specific antibodies, this specific antibodies can be attached to analyte and form the detectable compound of optics, for example by using fluorogen to come this analyte of mark, perhaps by the conjugate with the fluorogen mark was provided before optical detection.This detection can be undertaken by optical pickup, and this optical pickup can use excitation source to shine this chemical examination supporting substrate and can detect the fluorescence that sends from this fluorogen.
Optical assay is to be undertaken by the device for the optical evaluation that comprises sample support substrate and optical pickup.This optical pickup is included in the optical wavelength region (that is, between about 40nm to the 1mm source and the detector of) electromagnetic radiation, and be used to the suitable optical guide that focuses on and filter.This sample support comprises for example substrate of polymeric material, this substrate is provided with one or more reaction site-area (reaction site area), comprise for example point or the line of the tracer molecule of antibody, it is the binding site of target molecule that the analyte molecule that may be present in the sample is provided.When sample when tracer molecule on the stayed surface contacts, the target molecule in the sample will and form detectable point of optics or line with tracer molecule reaction on the substrate surface.When the excitation source of optical pickup shines this substrate, will launch light, show thus between the tracer molecule of the target molecule of sample and reaction site to react.
Light is perhaps launched with chemiluminescence with fluorescence or phosphorescent emissions.Fluorescence and phosphorescence may be defined as owing to the emission that excites the electromagnetic radiation that electromagnetic radiation causes that absorbs, and fluorescence is lasting less than 1 * 10 exciting after
-8Second, phosphorescence continues longer, and promptly decay is slower after being exposed to exciting light, and chemiluminescence is because the light emission that chemical reaction causes.
In fluorescence (and phosphorescence), the wavelength of exciting radiation is shorter than (that is, energy is higher than) emitted radiation usually, although also be correct conversely for multiphoton fluorescence.Can under stable state or time resolution, study the fluorescence behavior, and fluorescence spectrum comprises for example single photon or multiphoton fluorescence, FRET (FRET) and fluorescence up-conversion.In fluorescence assays, excite the type that depends on fluorogen with the wavelength of emitted radiation, this fluorogen can be the organic or inorganic source, for example cyanine dye or nanocrystalline.As example, use 649nm to excite common fluorogen Cy5 usually, and measure emission light at 670nm.
In optical assay, measure the intensity of emitting fluorescence or phosphorescence by the photodetector of optical pickup, can determine the concentration of analyte in the sample, can realize quantitative measurment thus.Therefore, excite the luminous efficiency of light-struck reaction site-area and the performance that radiative collection efficiency will influence optical assay.
In addition, the reaction site on the substrate surface can be provided with in conjunction with the point of the different tracer molecules of different target molecules or the array of line.Therefore, optical pickup can be designed to be able to determine by different fluorogens the existence of some analytes in the sample.
The scanning optical reader is for being used on the irradiated substrate detection site and being used to detect radiative conventional optical pickup device.The scanning optical reader preferably includes the narrowband excitation light source, laser for example, and this laser is focused on each detection site.Be focused on from the emission light of each detection site on the fluorescence detector of photodiode for example or PMT (photomultiplier).In the scanning optical reader, move the whole surface of scanning supporting substrate by the relative X-Y between Optical devices and support.The focusing arrangement of scanning optical reader can comprise the radiative confocal optics element in the depth of focus of for example only collecting object lens, for example stops unwanted light and reduces detection noise thus by pin hole.
The image optics reader is another kind of conventional optical pickup device, and it can detect two-dimensional array.This image optics reader comprises for example excitation source of xenon lamp, the most surfaces zone (or whole surf zone) that is used for irradiated substrate, and the detector of CCD (charge coupled device) imager for example, it can detect simultaneously from the emission light in whole detection site zone, and wherein this CCD imager utilizes MOS (metal on the semiconductor) technology and high quantum efficiency, sensitivity and spatial resolution is provided.In addition, wideband light source can be provided with wavelength filter so that monochromatic radiation to be provided.
WO 03/103835 has disclosed a kind of prior art sample support substrate that is used for fluid sample, and described substrate, is formed from the outstanding microtrabeculae pattern of substrate surface to be formed for the capillary flow path of sample by micro-structural.The size of microtrabeculae is at micrometer range, 1 micron (μ m)=1 * 10
-6M, and spacing is suitable for inducing the capillarity of liquid.In the device for the optical evaluation that comprises the sample support substrate that is provided with microtrabeculae, exciting light and radiative light path all will be subjected to the microtrabeculae influence, influence the performance of this device for the optical evaluation thus.The optical characteristics of baseplate material for example light transmission also will influence the performance of device for the optical evaluation.
WO 01/575501 has disclosed a kind of prior art optical pickup, wherein discloses the optical imagery without any the sample on the transparency carrier of outstanding microtrabeculae.This optical pickup comprises excitation energy source can detecting the emission of light from sample excitation, and this substrate is provided with the reflecting surface that is positioned under the sample and reflexes to checkout gear will launch light.
In addition, WO 2004/104585 has disclosed a kind of prior art device for the optical evaluation, and it relates to the microarray support of micro-structural, and wherein the height of this micro-structural is suitable for the depth of focus of this device for the optical evaluation.
The purpose of this invention is to provide the optical pickup and the polymeric sample substrate that are applicable to device for the optical evaluation, effective irradiation and the radiative effective collection and the detection of the reaction site-area by finishing substrate, and the optics background signal that reduces detection, increase signal to noise ratio thus, thereby realize improved optical assay performance.
Summary of the invention
Optical pickup, polymeric sample substrate and device for the optical evaluation by the foundation claims are realized these and other purposes.
The optical pickup that device for the optical evaluation is used comprises the light source that is used to shine the polymeric sample substrate with reaction-site surface, and this reaction-site surface comprises at least one reaction site-area that is provided with outstanding micro-structural.This optical pickup also comprises detector means, is used to detect the light from described at least one reaction site-area emission.This light source arrangement becomes excitation line is injected in this polymeric sample substrate by controlled incidence angle, select this controlled incidence angle to guide this excitation line to cause optical substrate properties along the direction of reaction site-area, this outstanding micro-structural has contribution to described optical substrate properties.
This polymeric substrates can be coated with the extra play with selected optical characteristics to small part, and this layer has contribution to this optical substrate properties.
This layer can be employed as the optics wetting layer, is arranged to increase the refraction angle of the excitation line of this substrate inside.
This extra play can cover the outstanding micro-structural and the load-bearing surface of this substrate to small part.
This extra play can be arranged to absorb selected optical wavelength, and can be made up of the band of the suitable material that is attached to this substrate.
The guiding device that this light source can be made as by the refraction angle that is arranged to control excitation line shines this polymeric sample substrate, and this guiding device can comprise prism or diffraction or the refraction grating of being located on the substrate surface.
In addition, this light source has the position that is associated with this polymeric sample substrate, to shine this reaction-site surface, load-bearing surface or the edge wall of this polymeric sample substrate.
This optical pickup can be arranged to make the refraction angle to surpass the critical angle of experiences total internal reflection in this polymeric sample substrate.
The detector means of this optical pickup can have the position that is associated with this polymeric sample substrate collecting reaction site-area emitted fluorescence or the phosphorescence from substrate, and should emission light can be by the direction of this optical substrate properties guiding along this detector means.
This detector means can have the position that is associated with this polymeric sample substrate, to receive the emitted fluorescence or the phosphorescence of escaping from the load-bearing surface or the edge wall of this substrate.
In addition, this light source can have first surface or the edge wall of position to shine this substrate that is associated with this polymeric sample substrate, and this detector means can have the position that is associated with this polymeric sample substrate, to receive from same first surface or edge wall or the emitted fluorescence or the phosphorescence of escaping from any other surface or the edge wall of this substrate.
This optical pickup can be arranged to the image optics reader or be arranged to the scanning optical reader.
This polymeric sample substrate that device for the optical evaluation is used has reaction-site surface, this reaction site surface comprises at least one reaction site-area that is provided with outstanding micro-structural, this substrate to small part is coated with the extra play with selected optical characteristics, adheres to the guiding device of the incidence angle of the light that is used to control this substrate of irradiation from the teeth outwards.
This extra play can cover the outstanding micro-structural and the load-bearing surface of this substrate to small part, and can be an optics wetting layer, is arranged to increase the refraction angle of the excitation line of this substrate inside.
In addition, described extra play can be arranged to absorb selected optical wavelength, and can be made up of the band of the suitable material that is attached to this substrate.
Described guiding device can comprise prism or diffraction or refraction grating.
By the of the present invention non-limiting embodiment disclosed in following description and the accompanying drawing and by claims, other features of the present invention and other advantage will be apparent.
Description of drawings
Now with reference to accompanying drawing the present invention is described in more detail, in the accompanying drawing:
Fig. 1 a illustrates the polymeric sample substrate that is provided with the outstanding micro-structural that forms microtrabeculae;
Fig. 1 b illustrates and is provided with the polymeric sample substrate that part is coated with the micro-structural of extra play;
Fig. 2 a and 2b illustrate the exemplary cross of microtrabeculae;
Fig. 3 illustrates the device for the optical evaluation that comprises scanning optical reader and polymeric substrates;
Fig. 4 illustrates the device for the optical evaluation that comprises image optics reader and polymeric substrates;
Fig. 5 a illustrates the incidence angle and the refraction angle of the excitation line that enters polymeric substrates;
Fig. 5 b is illustrated near the excitation line that enters polymeric substrates the substrate edges wall;
Fig. 6 illustrates the edge wall that is arranged to shine sample substrate and detects radiative optical pickup from the substrate reaction-site surface;
Fig. 7 illustrates the edge wall that is arranged to shine sample substrate and detects from the optical pickup of the light of base plate carrying surface emitting;
Fig. 8 illustrates the image optics reader that is arranged through grating irradiation sample substrate;
Fig. 9 illustrates the prism that is arranged through on the reaction-site surface that places substrate and shines this sample substrate and detect from the optical pickup of the light of this reaction-site surface emission;
Figure 10 illustrates the prism that is arranged through on the load-bearing surface that places substrate and shines this sample substrate and detect from the optical pickup of the light of the load-bearing surface emission of this substrate; And
Figure 11 illustrates the reaction-site surface that is arranged to shine sample substrate and detects from the optical pickup of the light of the edge wall emission of this substrate.
The specific embodiment
Use term and statement to have the normally used implication of those skilled in the art in specification and claims.
In addition, prefix " little (micro) " is used herein to a kind of device of definition, and this device comprises length, width or expresses (μ m, 1 * 10 with micron highly usually
-6M) at least one feature.
According to the present invention, by being provided with the polymeric substrates of outstanding micro-structural and selected optical substrate properties, and by comprising the optical pickup of light source and detector means, realize the improvement performance of device for the optical evaluation thus, the signal to noise ratio of Zeng Daing for example, wherein this light source can be injected into excitation line in this substrate by specific incidence angle, causes this optical substrate properties to guide this excitation line to propagate along the direction of the reaction site-area of substrate thus.
Fig. 1 a schematically shows first embodiment of the polymeric sample substrate of using according to device for the optical evaluation of the present invention 1, and this sample substrate is provided with the pattern of outstanding micro-structural 2, and this outstanding micro-structural can be arranged to be formed for the capillary flow path of this sample.The size of substrate preferably is adjusted into the suitable carrier of the one or more reaction site-area 5 that are formed for optical assay, and prior art microarray slide (slide) is rectangle, is of a size of 25mm * 75mm.The thickness of substrate can be for example about 1mm, and width and length for example between about 1mm to 100mm, form approximate rectangular or foursquare surf zone.The surface that is provided with the substrate of reaction site 5 becomes reaction-site surface 24 hereinafter, and another relative surface becomes load-bearing surface 26 hereinafter.In addition, this substrate has a plurality of edge wall, two edge wall 27a shown in this figure and 27b.Rectangle or foursquare substrate have four straight edge walls, but can have any other suitable shape alternatively according to the polymeric sample substrate of the other embodiment of the present invention, and for example crooked edge wall.The material of substrate is preferably the thermoplastic polymer with suitable optical characteristics, for example cycloolefine polymer or cyclenes copolymer, and this substrate can for example pass through casting by the polymer replication of parent structure (master structure) is made.
Fig. 2 a and 2b illustrate the exemplary cross of the outstanding micro-structural of supporting substrate, and this micro-structural forms microtrabeculae or microbot (micropost).Microtrabeculae can have any one of following shape for example: the arbitrary portion of circle, ellipse, rhombus, triangle, square, rectangle, heptagon, hexagonal cross-section or its combination or these shapes.
The present invention can be applicable to optical fluorescence/phosphorescence in conjunction with chemical examination, and is somebody's turn to do the performance that other optical characteristics of giving prominence to micro-structural and baseplate material will influence this optical assay.The material of polymeric substrates is preferably selected to obtain specific desired optical, the high optical transmittance in exciting light and radiative wave-length coverage only for example, and the high-absorbility of other wavelength, high and refractive index temperature stabilization, thereby provide improved focusing, low muddy (low haze) scattering and low birefringence.
The outstanding micro-structural of this substrate has contribution to the optical characteristics of substrate.This micro-structural all presents the optical focus characteristic for excitation line and emitting fluorescence.This micro-structure surface amplifies, and increases the ability that excites of substrate owing to the increase of photon number in the face coat.When being labeled as fluorescence, because the photon number of launching from the fluorochrome that arrives the optical detection system increases, the emissivities that support increase, and, avoid unwanted background fluorescence to realize the minimizing of noise by reducing the number that advances/go out the photon of substrate supported.Therefore, be provided with outstanding micro-structural for example the optical characteristics of the polymeric substrates of microtrabeculae recently influence the performance of optical assay by increasing noise.
The present invention relates to be applicable to the optical pickup of the device for the optical evaluation that comprises above-mentioned polymeric sample substrate, this polymeric sample substrate is provided with for example pattern of microtrabeculae of outstanding micro-structural.The amplification of the support surface area that is caused by microtrabeculae and increased detected signal forms more binding site, and therefore forms stronger fluorescence signal.This microtrabeculae also causes the hydrophobic behavior of the enhancing of this substrate surface, because compare with planar polymer, the angle of wetting of structurized polymer is bigger, helps for example printing of the high-density micro-array of spike point.The optical characteristics of polymeric substrates is subjected to the influence of the configuration of micro-structural, for example the shape of this microtrabeculae, highly, the influence of width, thickness and spacing.
In addition, this polymeric sample substrate can be provided with extra play, this extra play chosen optics behavior and selected optical characteristics with the expectation that realizes this substrate.This layer can be applied on the reaction-site surface or on the load-bearing surface, perhaps be applied on these two, and on one or more edge wall of this substrate, cover whole edge wall or edge wall or surface surperficial or only part, and this layer can be applied on this outstanding micro-structural, covers this micro-structural to small part.In addition, this extra play can be an arbitrary shape, and it can make unevenly, form by for example little particle or pyramid, or uniformly.This layer also comprises the embossment structure that forms diffraction or refraction grating.The material of this layer, thickness and uniformity preferably are selected as providing reflectivity, transmissivity or the absorptivity to exciting light, emission light or the expectation of the two, and chosen " beam dump (the beam dump) " that will produce optical radiation with the material layer of realizing high optical absorptivity and thickness.This extra play for example can be employed film forming, band, coating, fluid or gel, and can comprise organic or inorganic material, for example metal, dielectric or semi-conducting material, polymer or pottery, and can further comprise pigment or dyestuff.In addition, this extra play can be the optics wetting layer, uses this optics wetting layer and makes not have air between this layer and the surface.If the refractive index of the material of this layer greater than aerial refractive index, then can realize the increase at the refraction angle of excitation line in the inside of this substrate.
Fig. 1 b illustrates according to of the present invention, be provided with second embodiment of the polymeric sample substrate 1 of extra play 31a, 31b as mentioned above, the whole planar section of the reaction-site surface 24 of the 31a of the first covered substrate of this extra play wherein, second portion 31b covers the end face of microtrabeculae 2.
Yet, in order to utilize the optical characteristics of above-mentioned selected polymeric substrates, to dispose and by specific incidence angle excitation line to be injected light source in the polymeric substrates according to optical pickup of the present invention, this light source is chosen so that the optical characteristics of the polymeric substrates of this device for the optical evaluation guides light to propagate towards reaction site-area, cause exciting light more effectively to shine reaction site thus, thereby improve the performance of optical assay.
Embodiment again according to optical pickup of the present invention, improve the performance of this optical assay by the detector means of this optical pickup, wherein this detector means can detect by the optical characteristics of this polymeric substrates emission light along the direction guiding of detector means.
Fig. 3 illustrates the exemplary assembling of the device for the optical evaluation that comprises scanning optical reader 3 and polymeric sample substrate 1, and wherein this polymeric sample substrate 1 is provided with the reaction site-area 5 of micro-structural.It is movably that this sample substrate is arranged to respect to this optical pickup, makes the entire reaction site areas 5 of sample substrate be scanned.This scanning optical reader comprises excitation source 6 and detector means 7, wherein this excitation source 6 is positioned at the position with the load-bearing surface 26 of irradiated substrate, and this detector means 7 is PMT for example, is positioned at the position of collection from the light of reaction-site surface 24 emissions of substrate.This optical pickup also comprises lens 8 and 9 and optical filter 10, and these lens 8 and 9 are used for focusing on exciting light on this substrate and being used for emission light is focused on detector.
Fig. 4 illustrates the exemplary assembling of the device for the optical evaluation that comprises image optics reader 13 and polymeric sample substrate 1, and wherein this polymeric sample substrate 1 is provided with the reaction site-area 5 with outstanding microtrabeculae 2.This image optics reader comprises excitation source 11 and detector means 12, wherein this excitation source 11 is placed the position of the whole load-bearing surface 26 of this substrate of irradiation, and this detector means 12 is for example placed the radiative position of detecting simultaneously from entire reaction site areas 5 for CCD.This image optics reader also is provided with lens 13 and optical filter 14, and wherein these lens 13 are used for emission light gathering and focus on detector 12.
In order to realize the improved performance of device for the optical evaluation, can place the position that is associated with polymeric substrates according to optical pickup of the present invention, so that excitation line is injected described substrate by controlled incidence angle, this controlled incidence angle is chosen as and makes the optical characteristics of this substrate guide this excitation line along the direction of reaction site.
According to an embodiment of this optical pickup, thereby shine the incidence angle that this substrate is realized expectation by guiding device, this guiding device for example for place on the reaction-site surface, on the load-bearing surface or prism or grating on the edge wall of substrate.
According to the embodiment again of optical pickup of the present invention, this checkout gear can place the position that is associated with polymeric sample substrate, thereby detects along the direction of this checkout gear emission light that optical characteristics guided by described substrate.
In order to explain notion of the present invention, Fig. 5 a illustrates the light 28 that is injected in the polymeric sample substrate 1, and this light 28 is formed into firing angle 29 with the normal 25 of substrate surface 24, and incidence angle 29 depends on the position of light source (not shown) with respect to substrate.The light of injecting can be aggregated the refraction of thing substrate to form refraction angle 30 in substrate inside with respect to normal 25, and the refractive index of baseplate material is depended at this refraction angle 30.When incidence angle 29 is chosen as when making the refraction angle 30 of refracted ray of substrate inside equal or exceed the critical angle of experiences total internal reflection in this substrate when optical condition allows, excitation line will be propagated by total internal reflection in substrate, as shown by arrows.
Fig. 5 b illustrates two exemplary configuration by light source 6a, 6b with further explanation notion of the present invention, and this light source arrangement becomes near substrate edges wall 27a, 27b excitation line to be injected in substrate 1a, the 1b.
The first light source 6a is positioned at the position of light directly being injected the edge wall 27a of the first substrate 1a, and the incidence angle of this light makes in this substrate the total internal reflection that excitation line takes place.
Secondary light source 6b is positioned at the position of the end face 24b that launches light into the second substrate 1b.Light is launched into the second substrate 1b at the point near the edge wall 27b of substrate by prism 22, and this prism 22 places surperficial 24b to go up incidence angle with control light, makes the total internal reflection that excitation line takes place in substrate 1b.
The total internal reflection that takes place in substrate 1a and 1b will produce evanescent field on the border between polymeric substrates and the air, this evanescent field extends into air about 300 to 400nm, and can effectively excite the fluorogen of the reaction site (not shown) of being located on the substrate.
Yet according to other embodiments of the invention, incidence angle is chosen as and makes the critical angle be not equal to or surpass total internal reflection, and incidence angle for example may be selected to be with normal and become zero degree, that is, impact light and be parallel to normal 25.
Fig. 6 illustrates first embodiment of optical pickup 33 of the present invention, and the polymeric sample substrate 1 with reaction-site surface 24 and edge wall 27 is shown, and this reaction-site surface 24 is provided with the reaction site-area 5 of micro-structural.Optical pickup 33 comprises lens 8,9 and optical filter 10, and the light source 6 that is set to excitation line is injected substrate edges 27, and this light is focused on this edge by lens 8.The guiding property of the refractive index of the configuration of light source 6, substrate 1 and lens 8 will influence this light, realize launching light into this substrate with controlled incidence angle.The light of injecting for example is directed by the reflection of substrate inwall in substrate, thereby propagates the also fluorogen in provocative reaction site towards reaction site-area 5.To be focused on by lens 9 from the light of reaction site-area emission, be filtered, and be collected by the optical detection device 7 that for example is PMT by filtering apparatus 10.
Fig. 7 illustrates second embodiment of optical pickup 43 of the present invention, and the assembling similar to optical pickup shown in Figure 6 33 is shown.Yet according to second embodiment, checkout gear 7 has the position that is associated with polymeric sample substrate 1 detecting the emission light of escaping from the load-bearing surface 26 of described substrate 1, rather than the emission light of escaping from reaction-site surface 24.According to this second embodiment, the light of injecting will be propagated towards reaction site-area 5, the fluorogen in provocative reaction site, and will be by lens 9, filtering apparatus 10 substrate 1 is passed in transmission after and for example be optical detection device 7 collections of PMT from the light of fluorogen emission.By being provided with to detect the radiative detector that transmission is passed substrate and escaped from load-bearing surface 25, can detect the fluorescence signal of increase, increase signal to noise ratio thus.Owing to the following fact is reached this point: under given conditions, from the fluorescence of fluorogen in the part of substrate internal emission greater than the part of in air, launching.
Fig. 8 illustrates the 3rd embodiment of optical pickup 53 of the present invention, this optical pickup 53 is the image optics reader of device for the optical evaluation, this optical pickup comprises the polymeric sample substrate 1 according to third embodiment of the invention, has reaction site surface 24 and load-bearing surface 26.This reaction-site surface comprises the reaction site-area 5 that is provided with microtrabeculae 2, and load-bearing surface 26 is provided with grating 21a, the 21b incidence angle with the control excitation line.This optical grating construction is a surface relief, and it can be diffraction or refractive properties.Light source 11 is arranged through described grating 21a and 21b and shines the whole zone of the load-bearing surface 26 of this substrate, described grating 21a and 21b are made as and adjoin this edge wall 27a and 27b, and the optical characteristics of grating will influence the incidence angle that the light of described grating 21a and 21b is passed in transmission.Therefore, this grating will reflect or this light of diffraction, realize the controlled incidence angle of this light, make that impacting light will be directed toward reaction site-area 5 in substrate.Yet the light that impacts on the surface 26 between the described grating of adjoining reaction site areas 5 will be arranged essentially parallel to surface normal, and direct transmission is passed this substrate to this reaction site-area.Thus, can realize very effective irradiation to reaction site-area.
Fig. 9 is illustrated in the 4th embodiment of the optical pickup of the present invention 63 in the device for the optical evaluation of the 4th embodiment that comprises polymeric sample substrate 1, have reaction-site surface 24, load-bearing surface 26 and edge wall 27, substrate 1 is provided with the zone, reaction position 5 of micro-structural on reaction-site surface 24, and extra play 31 is located on the part load-bearing surface 26.Light source 6 has the position that is associated with this polymeric sample substrate, with the reaction site surface 24 that places the leaded light prism 22 on the surface 24 to come irradiated substrate by edge-adjacent wall 27.The configuration of light source 6 and the refracting characteristic of prism will provide the light of injecting with controlled incidence angle, and this light will be by the direction guiding along orientating reaction site areas 5 of substrate and extra play 31.To be collected and detect by lens 9, optical filter 10 and detector 7 from the light of reaction site emission.
Figure 10 illustrates the 5th embodiment of optical pickup 73 of the present invention, has disclosed the device for the optical evaluation with assembling similar to the optical pickup 63 of the 4th embodiment shown in Figure 9.Yet, according to the 5th embodiment, checkout gear 7 has the position that is associated with polymeric sample substrate 1, to detect the emission light from the load-bearing surface 26 of described substrate 1, rather than from the emission light of reaction-site surface 24, and this substrate is not provided with any semi-reflective layer.In addition, light source 6 has the position that is associated with polymeric sample substrate 1, thereby comes the load-bearing surface 26 (but not reaction-site surface 24) of irradiated substrate by the leaded light prism 22 of surface on 26 that place of edge-adjacent wall 27.The configuration of light source 6 and the refracting characteristic of prism will provide the light of injecting with controlled incidence angle, and this light will be propagated towards reaction site-area 5 by substrate-guided, excite the fluorogen of being located on the reaction site.Because most fluorescent emission are in substrate inside rather than air, the overwhelming majority is passed substrate 1 from the light of fluorogen emission with transmission, by lens 9, filtering apparatus 10 and for example optical detection device 7 collections of PMT.
Figure 11 illustrates the 6th embodiment of optical pickup 83 of the present invention, and the 5th embodiment of polymeric sample substrate 1, and it has the reaction-site surface 24 of the reaction site-area 5 that is provided with micro-structural, and whole load-bearing surface 26 is coated with extra play 31.Optical pickup 83 comprises light source 6 and checkout gear 7, this light source 6 is placed so that excitation line is directly injected reaction site-area 5 with respect to polymeric sample substrate 1, and this checkout gear 7 is placed the emitted fluorescence of escaping from edge wall 27 to receive with respect to this polymeric sample substrate 1.Excitation line from light source impacts on surface 24, and this excitation line is guided by lens 8, the approximate normal of direction corresponding to surface 24, that is and, incidence angle is smaller, for example less than 10 °.Light is with the fluorogen in the provocative reaction site, and most emitted fluorescence will be along various different directions transmission in substrate.Emission light will be from substrate inner surface and the inner surface reflection of being located at the additional semi-reflective layer 31 on the load-bearing surface 26 of substrate, make the part emitted fluorescence be directed along the direction of edge wall 27, scioptics 9 and optical filter 10 detected devices 7 are collected, and wherein this checkout gear 7 is arranged to receive the light of escaping from edge wall 27.
According to the 6th embodiment of polymeric sample substrate of the present invention, on the surface of leaded light prism 22 attached to substrate.
Six embodiments of the optical pickup of the present invention shown in Fig. 6 to 11 show the light source 6 that is associated with the position of polymeric sample substrate 1 and the exemplary configuration of detector means 7 positions.Yet other embodiments according to the present invention, light source 6 can be changed to be injected excitation line in any one of two surfaces 24,26, perhaps injects in arbitrary edge wall 27 of substrate.Similarly, according in addition other embodiments of the present invention, checkout gear 7 can be changed to detection from any one of two surfaces 24 or 26, the perhaps fluorescence or the phosphorescence of escaping from arbitrary edge wall 27.
In addition, light source 6 and detector means 7 can be changed to and inject excitation line and detect from same surface or edge wall or from the emission light of different surfaces or edge wall.
Therefore, the invention is not restricted to the described embodiment in the accompanying drawing, and can freely change within the scope of the appended claims.
Claims (31)
1. the optical pickup (33 that is used for device for the optical evaluation, 43,53,63,73,83), this optical pickup comprises the light source (6 that is used for shining the polymeric sample substrate (1) with reaction-site surface (24), 11), this reaction-site surface (24) comprises at least one reaction site-area (5) that is provided with outstanding micro-structural (2), this optical pickup also comprises detector means (7,12), be used to detect light from described at least one reaction site-area emission, it is characterized in that: described light source (6,11) be arranged to excitation line (28) is injected in this polymeric sample substrate (1) by controlled incidence angle (29), select this controlled incidence angle to guide this excitation line to cause optical substrate properties along the direction of reaction site-area (5), described outstanding micro-structural (2) is arranged such that this outstanding micro-structural influences described optical substrate properties.
2. optical pickup as claimed in claim 1 is characterized in that: this polymeric sample substrate (1) to small part is coated with the extra play (31) of the described optical substrate properties of influence.
3. optical pickup as claimed in claim 2 is characterized in that: described extra play (31) is used as the optics wetting layer, be arranged to increase the refraction angle (30) of this excitation line.
4. as claim 2 or 3 described optical pickups, it is characterized in that: described extra play (31) to small part covers should outstanding micro-structural (2).
5. optical pickup as claimed in claim 2 is characterized in that: described extra play (31) to small part covers the load-bearing surface (26) of this substrate (1).
6. optical pickup as claimed in claim 2 is characterized in that: described extra play (31) is arranged to absorb selected optical wavelength.
7. optical pickup as claimed in claim 2 is characterized in that: described extra play (31) is made up of the band of the suitable material that is attached to this substrate (1).
8. optical pickup as claimed in claim 1 is characterized in that: described light source (6) is made as by being arranged to control the guiding device (21,22) of this excitation line at the refraction angle (30) of this substrate inside and shines this polymeric sample substrate (1).
9. optical pickup as claimed in claim 8 is characterized in that: described guiding device comprises the reaction-site surface (24) of being located at this substrate or the prism (22) on the load-bearing surface (26).
10. optical pickup as claimed in claim 8 is characterized in that: described guiding device comprises reaction-site surface (24) or diffraction on the load-bearing surface (26) or the refraction grating (21) of being located at this substrate.
11. optical pickup as claimed in claim 1 is characterized in that: this light source (6,11) has the position that is associated with this polymeric sample substrate (1), with the reaction-site surface (24) of shining described substrate.
12. optical pickup as claimed in claim 1 is characterized in that: this light source (6,11) has the position that is associated with this polymeric sample substrate (1), with the load-bearing surface (26) that shines described substrate.
13. optical pickup as claimed in claim 1 is characterized in that: this light source (6) has the position that is associated with this polymeric sample substrate (1), with the edge wall (27) of shining described substrate.
14. optical pickup as claimed in claim 1 is characterized in that: adopt a kind of layout, make this refraction angle (30) surpass the critical angle of experiences total internal reflection in this polymeric sample substrate (1)
15. optical pickup as claimed in claim 1, it is characterized in that: described detector means (7,12) have the position that is associated with this polymeric sample substrate (1) collecting zone, reaction position (5) emitted fluorescence or phosphorescence from substrate (1), from the light of described at least one reaction site-area emission by of the direction guiding of this optical substrate properties along this detector means.
16. optical pickup as claimed in claim 1 is characterized in that: described detector means (7,12) has the position that is associated with this polymeric sample substrate (1), to receive the emitting fluorescence or the phosphorescence of escaping from the load-bearing surface (26) of this substrate.
17. optical pickup as claimed in claim 1 is characterized in that: described detector means (7,12) has the position that is associated with this polymeric sample substrate (1), to receive the emitting fluorescence or the phosphorescence of escaping from the edge wall (27) of this substrate.
18. optical pickup as claimed in claim 1, it is characterized in that: described light source (6) has the position that is associated with this polymeric sample substrate (1) with surface in irradiation reaction-site surface (24) and the load-bearing surface (26) or edge wall (27), and this detector means (7,12) has the position that is associated with this polymeric sample substrate (1), to receive the emitting fluorescence or the phosphorescence of from reaction-site surface (24) and load-bearing surface (26) same surface or edge wall (27) escape.
19. optical pickup as claimed in claim 1, it is characterized in that: described light source (6) has the position that is associated with this polymeric sample substrate (1) with surface in irradiation reaction-site surface (24) and the load-bearing surface (26) or edge wall (27), and this detector means (7,12) has the position that is associated with this polymeric sample substrate (1), to receive the emitting fluorescence or the phosphorescence of from reaction-site surface (24) and load-bearing surface (26) another one surface or edge wall (27) escape.
20. optical pickup as claimed in claim 1 is characterized in that: this optical pickup is arranged to the image optics reader.
21. optical pickup as claimed in claim 1 is characterized in that: this optical pickup is arranged to the scanning optical reader.
22. the polymeric sample substrate that device for the optical evaluation is used (1), this polymeric sample substrate has reaction-site surface (24), this reaction-site surface (24) comprises at least one reaction site-area (5) that is provided with outstanding micro-structural (2), this substrate (1) to small part is coated with extra play (31), be somebody's turn to do outstanding micro-structural and extra play and influence this optical substrate properties, it is characterized in that: guiding device (21,22), be used for the incidence angle (29) of the light of control this substrate of irradiation (1) attached on the reaction-site surface (24).
23. polymeric sample substrate as claimed in claim 22 (1) is characterized in that: described extra play (31) to small part covers the outstanding micro-structural (2) of this substrate (1).
24. as claim 22 or 23 described polymeric sample substrate (1), it is characterized in that: described extra play (31) to small part covers the load-bearing surface (26) of this substrate (1).
25. polymeric sample substrate as claimed in claim 22 (1) is characterized in that: described extra play (31) is applied as the optics wetting layer, is arranged to increase the refraction angle (30) of this excitation line.
26. polymeric sample substrate as claimed in claim 22 (1) is characterized in that: described extra play (31) is arranged to absorb selected optical wavelength.
27. polymeric sample substrate as claimed in claim 22 (1) is characterized in that: described extra play (31) is made up of the band of the suitable material that is attached to this substrate (1).
28. polymeric sample substrate as claimed in claim 22 (1) is characterized in that: described guiding device comprises prism (22).
29. polymeric sample substrate as claimed in claim 22 (1) is characterized in that: described guiding device comprises diffraction or refraction grating (21).
30. be suitable for as any described optical pickup (33 of claim 1 to 21,43,53,63,73,83) polymeric sample substrate (1), this polymeric sample substrate (1) is provided with outstanding micro-structural (2), and described outstanding micro-structural (2) is arranged such that this outstanding micro-structural influences described optical substrate properties.
31. device for the optical evaluation, it comprises as any described optical pickup of claim 1 to 21 (33,43,53,63,73,83) with as any described polymeric sample substrate (1) that is provided with outstanding micro-structural (2) of claim 22 to 30.
Applications Claiming Priority (4)
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| SE0501397A SE529254C2 (en) | 2005-06-17 | 2005-06-17 | Optical test system |
| SE0501397-4 | 2005-06-17 | ||
| SE05013974 | 2005-06-17 | ||
| PCT/SE2006/000671 WO2006135306A1 (en) | 2005-06-17 | 2006-06-08 | Optical assay system |
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| CN101180128A CN101180128A (en) | 2008-05-14 |
| CN101180128B true CN101180128B (en) | 2011-08-03 |
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| EP (1) | EP1912740B1 (en) |
| JP (2) | JP2008546997A (en) |
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| BR (1) | BRPI0612743B1 (en) |
| SE (1) | SE529254C2 (en) |
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- 2006-06-08 EP EP06747864.4A patent/EP1912740B1/en active Active
- 2006-06-08 WO PCT/SE2006/000671 patent/WO2006135306A1/en active Application Filing
- 2006-06-08 CN CN200680017677XA patent/CN101180128B/en active Active
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- 2006-06-15 US US11/454,993 patent/US7564045B2/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1482479A (en) * | 2002-08-15 | 2004-03-17 | Hoya株式会社 | Optical branching and inserting module |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1912740B1 (en) | 2016-04-27 |
| JP2008546997A (en) | 2008-12-25 |
| BRPI0612743B1 (en) | 2017-06-06 |
| JP2013019907A (en) | 2013-01-31 |
| US7564045B2 (en) | 2009-07-21 |
| BRPI0612743A2 (en) | 2010-11-30 |
| EP1912740A1 (en) | 2008-04-23 |
| SE0501397L (en) | 2006-12-18 |
| EP1912740A4 (en) | 2012-01-11 |
| AU2006258283B2 (en) | 2011-07-28 |
| AU2006258283A1 (en) | 2006-12-21 |
| WO2006135306A1 (en) | 2006-12-21 |
| SE529254C2 (en) | 2007-06-12 |
| CN101180128A (en) | 2008-05-14 |
| US20060289787A1 (en) | 2006-12-28 |
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